Flexible member for use as a medical bag

ABSTRACT

According to the present invention, there is provided a highly biodegradable flexible member adapted for medical use which is capable of undergoing degradation in a relatively short period of time in natural environment by burying in soil or abandoning in sea after its sterilization so that no environmental pollution would be caused by its disposal, and which additionally has excellent workability, cost performance, compatibility to ecosystem, as well as biocompatibility. At least a portion of the flexible medical member is fabricated from a material containing a resin composition comprising a polyhydroxyalkanoate, a copolymer thereof, or a mixture thereof as its main component, and 0.01 to 60% by weight of a lipid compound.

TECHNICAL FIELD

This invention relates to a flexible member for medical use havingbiodegradability as well as excellent physical properties includingflexibility, impact resistance and workability.

BACKGROUND ART

Conventional flexible materials which have been used for medicalpurposes include materials mainly comprising polyvinyl chloride havingblended therein a plasticizing agent selected from phthalic acid-basedcompounds such as dioctyl phthalate and 2-ethylhexyl phthalate in anamount of from 10 to 100% by weight per 100% by weight of the polyvinylchloride; materials mainly comprising an elastomer resin such as astyrene-butadiene-styrene-based resin, for example an ABA-type blockcopolymer, an ethylene-propylene copolymer, a polyester elastomer or apolyurethane elastomer; and flexible resins such as an ethylene-vinylacetate copolymer and an ethylene-ethylacrylate copolymer.

Most of the flexible medical members fabricated from such materials, forexample, blood bags, tubes, catheters and the like, are disposableproducts, and after their use, they are abandoned as waste materials.These materials, however, do not undergo environmental degradation andretain their original shape for a prolonged period of time. It is wellknown that such waste materials have induced various social problemsincluding the pollution.

In order to solve such problems, various investigations have beenrecently carried forward to develop biodegradable materials, namely,high molecular weight materials capable of being decomposed in ecosystemwhen placed or abandoned in the environment, and these materials haveattracted a considerable public attention.

Of the conventionally known high molecular weight biodegradablematerials, those comprising polypropylene, polyethylene or the likehaving blended therein corn starch for the purpose of theirmorphological collapse can not be deemed essentially biodegradable,since these materials only experience morphological change with thelapse of time, and the high molecular weight backbone of thepolypropylene or polyethylene do not undergo any degradation.

Another group of biodegradable materials known in the art arepoly(3-hydroxybutyrate) and copolymers mainly comprising thepoly(3-hydroxybutyrate). Poly(3-hydroxybutyrate) is a material which hasbeen confirmed to undergo a considerable environmental degradation, andto have an excellent biocompatibility. Therefore, this material washighly expected to have various applications in medical and otherfields.

Contrary to such expectations, the poly(3-hydroxybutyrate) failed tofind a large number of applications due to insufficiency in its impactresistance and other physical properties because of its hardness andbrittleness. The poly(3-hydroxybutyrate) is also poor in its workabilitysince it undergoes decomposition in the vicinity of its melting point inspite of its useful thermoplasticity.

In view of such conditions, various attempts have been made to modifythe physical properties of the poly(3-hydroxybutyrate). Japanese PatentApplication Kokai No. 63(1988)-269989 discloses a copolymer comprisingrecurring structural units of D-(-)3-hydroxybutyrate andD-(-)3-hydroxyvalerate. This material has attained considerableimprovements in reducing melting point and in increasing flexibility.Synthesis of this material, however, could be effected only at a lowproductivity, and also, required a special substrate for thefermentation. As a consequence, this copolymeric material was ratherexpensive to detract from its availability as a general-purposematerial.

Other attempts of altering the physical properties of thepoly(3-hydroxybutyrate) include modification of thepoly(3-hydroxybutyrate) by mixing with such resin materials aspolyethylene oxide, ethylene propylene rubber, and polyvinyl acetate.None of the attempts, however, have fully succeeded in providing thestability, cost performance, workability, and the like with theresulting resin compositions. Use of such resin compositions for medicalapplications would be even more difficult since such applications wouldfurther require high safety and hygienic properties.

SUMMARY OF THE INVENTION

An object of the present invention is to obviate the above-describedproblems of the prior art by using a predetermined resin composition asa material for fabricating the flexible medical member, and therebyprovide a highly biodegradable flexible member for medical use which iscapable of undergoing degradation in a relatively short period of timein natural environment by burying in soil or abandoning in sea after itssterilization so that no environmental pollution would be caused by itsdisposal, and which additionally has excellent biocompatibility,compatibility to ecosystem, workability as well as cost performance.

Such an object is achieved by the present invention as described below.

According to the present invention, there is provided a flexible memberfor medical use which is characterized in that at least a portion of themember is prepared from a material containing a resin compositioncomprising a polyhydroxyalkanoate, a copolymer thereof, or a mixturethereof as its main component, and 0.01 to 60% by weight of a lipidcompound.

The polyhydroxyalkanoate may preferably be at least a member selectedfrom poly(3-hydroxyalkanoate)s, poly(4-hydroxyalkanoate)s, andpoly(5-hydroxyalkanoate)s.

It is preferable that the flexible medical member has a tubularconfiguration to constitute at least a part of a member, for example, aninfusion system, a blood transfusion system, a blood circulationcircuit, or a catheter.

It is also preferable that the flexible medical member is a member inthe form of a bag, for example, a blood bag, an infusion bag, a dialysisbag, or a perintestinal nutrient bag.

Furthermore, it is preferable that the flexible medical member is amember in the form of a thread, a woven fabric, or a nonwoven fabric,for example, a suture, a mesh, a patch, a pledget, and a prosthesis.

Still further, it is preferable that the flexible medical member is amember selected from a staple, a clip and a coalescence-preventingmembrane.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 a diagram showing number average molecular weight of thepoly(3-hydroxybutyrate) in relation to dose of the γ-ray irradiated.

FIG. 2 a diagram showing number average molecular weight of thepoly(3-hydroxybutyrate) in relation to period of the heat treatment.

FIG. 3 is a schematic view of an example of a staple which is anembodiment of the flexible medical member according to the presentinvention.

FIG. 4 is a schematic view of an example of an infusion system havingemployed therein a flexible tube, which is an embodiment of the flexiblemedical member according to the present invention.

FIG. 5 is a schematic view of an example of a flexible bag which is anembodiment of the flexible medical member according to the presentinvention.

BEST MODE FOR CARRYING OUT THE INVENTION

The flexible member for medical use according to the present inventionis hereinafter described in further detail.

The flexible member for medical use of the present invention is a memberwherein at least a part of the member comprises a resin compositionbasically comprising a polyhydroxyalkanoate, a copolymer thereof, or amixture thereof, and further comprising from 0.01 to 60% by weight of alipid compound; a complex material comprising a mixture of such a resincomposition with another resin; or a processed material comprising suchas a resin composition and another resin material. Such a flexiblemember for medical use of the present invention is suitable for variousmedical members including those which have been conventionallyfabricated from the above-mentioned flexible material comprisingpolyvinyl chloride having added thereto dioctyl phthalate, for example,a blood bag, an infusion bag, a dialysis bag, a perintestinal nutrientbag, and the like, and various tubings and manifolds to be connected tosuch bags, as well as catheters, and the like; those fabricated fromthread-like products, and woven and nonwoven fabrics, for example, asuture, a mesh, a patch, a pledget, a prosthesis, and the like; andthose requiring non-brittleness as well as flexibility, for example, astaple and a clip. Among these, the flexible medical member of thepresent invention is particularly suitable for a disposable medicalmember.

Such a flexible member for medical use of the present invention isinexpensive, and has sufficient productivity, flexibility, corrosionresistance, workability, cost performance, compatibility to ecosystem,biocompatibility, as well as excellent biodegradability to cause noenvironmental pollution after its disposal.

The flexible member for medical use of the present invention basicallycomprises a highly biodegradable resin composition comprising apolyhydroxyalkanoate, a copolymer thereof, or a mixture thereof as itsmain component, and 0.01 to 60% by weight of a lipid compound.

The polyhydroxyalkanoates which may be used in the present inventioninclude those comprising recurring units of a hydroxyalkanoate havingabout 3 to 12 carbon atoms. Preferable examples of thepolyhydroxyalkanoate include poly(3-hydroxyalkanoate)s such aspoly(3-hydroxypropionate), poly(3-hydroxybutyrate),poly(3-hydroxyvalerate), poly(3-hydroxyoctanoate), etc;poly(4-hydroxyalkanoate)s such as poly(4-hydroxybutyrate),poly(4-hydroxyvalerate), etc; and poly(5-hydroxyalkanoate)s such aspoly(5-hydroxyvalerate), etc.

Among these, poly(3-hydroxybutyrate) may most preferably be used in thepresent invention.

In the present invention, not only the use of homopolymers of thehydroxyalkanoate, but also the use of copolymers of thehydroxyalkanoates are preferable.

Exemplary copolymers of the hydroxyalkanoates include copolymers of3-hydroxybutyrate with another hydroxyalkanoate having 3 to 12 carbonatoms. Non-limiting preferable examples include(3-hydroxybutyrate)-(3-hydroxypropionate) copolymer,(3-hydroxybutyrate)-(3-hydroxypropionate)-(4-hydroxybutyrate) copolymer,(3-hydroxybutyrate)-(3-hydroxyvalerate) copolymer,(3-hydroxybutyrate)-(3-hydroxyvalerate)-(3-hydroxyhexanoate)-(3-hydroxyheptanoate)-copolymer,(3-hydroxybutyrate)-(3-hydroxyvalerate)-(3-hydroxyhexanoate)-(3-hydroxyheptanoate)-(3-hydroxyoctanoate)copolymer, (3-hydroxybutyrate)-(3-hydroxyhexanoate)-(3-hydroxyoctanoate)copolymer, (3-hydroxyoctanoate)-(3-hydroxylaurate) copolymer,(3-hydroxybutyrate)-(4-hydroxydibutyrate) copolymer,(3-hydroxybutyrate)-(4-hydroxyvalerate) copolymer, and(3-hydroxybutyrate)-(5-hydroxyvalerate) copolymer.

In the present invention, use of a mixture of the above-mentionedpolyhydroxyalkanoates, a mixture of the above-mentioned copolymers, aswell as a mixture of the above-mentioned polyhydroxyalkanoate and theabove-mentioned copolymer are also preferred.

As is well known in the art, the polyhydroxyalkanoates and theircopolymers are produced by various microorganisms. Those produced by anymicroorganism may be employed in the present invention.

Chemically synthesized polyhydroxyalkanoates and copolymers thereof mayalso be used in the present invention.

The microorganisms which produce a polyhydroxyalkanoate include, forexample, various species of bacteria belonging to Acinetobacter,Actinomycetes, Alcaligenes, Aphanothese, Aquaspirillum, Azospirillum,Azotobacter, Bacillus, Beggiatoa, Beijerinckia, Caulobacter,Chlorofrexeus, Chlorogloea, Chromatium, Chromobacterium, Clostridium,Derxia, Ectothiorhodospira, Echerichia, Ferrobacillus, Gamphosphaeria,Haemophilus, Halobacterium, Hyphomicrobium, Lamprocystis, Lampropedia,Leptothrix, Methylobacterium, Methylocystis, Micrococcus, Microcoleus,Microcystis, Moraxella, Mycoplana, Nitrobacter, Nitrococcus, Nocardia,Oceanospirillum, Paracoccus, Photobacterium, Pseudomonas, Rhizobium,Rhodobacter, Rhodospirillum, Sphaerotilus, Spirillum, Spirulina,Streptomyces, Syntrophomonas, Thiobacillus, Thiocapsa, Thiocystis,Thiodictyon, Thiopedia, Thiosphaera, Vibrio, Xanthobacter, Zoogloea, andthe like.

The polyhydroxyalkanoate or its copolymer synthesized by fermentationgenerally has a number average molecular weight, Mn of about 3,000 to3,000,000. Use of a polyhydroxyalkanoate or its copolymer which has beenpost-treated by heating or γ-ray irradiation after its synthesis byfermentation to reduce its molecular weight to, for example, about 3,000to 10,000 is also preferable.

By using a 3-hydroxyalkanoate and/or 4-hydroxyalkanoate (β- orγ-hydroxyalkanoate) polymer having a number average molecular weight of10,000 to 200,000, and preferably 30,000 to 100,000 for the maincomponent of the resin composition, the period of decrease in themechanical strength or degradation of the material itself throughhydrolysis in a living body may be adjusted within the range of fromseveral months to several years. Consequently, the resin composition canbe suitably employed for a flexible medical member to be buried in aliving body which should retain its action for a relatively prolongedperiod of time, for example, a suture, a prosthesis, acoalescence-preventing material, and the like.

When the resin composition is used for a member to be buried in a livingbody, and the polyhydroxyalkanoate has a number average molecular weightof more than 200,000, the period required for undergoing decrease in themechanical properties through in vivo hydrolysis would be excessivelylong such that the buried material would not substantially undergo asufficient degradation while the material is in its use. On the otherhand, when the polyhydroxyalkanoate has a number average molecularweight of less than 10,000, the resin composition would not have astrength required for an implanted member.

Adjustment of the molecular weight can be effected by a post-treatment,for example, a heat treatment or a γ-ray irradiation.

A polyhydroxyalkanoate would undergo a decrease in its molecular weightwhen irradiated with an ionizing radiation, and in particular, γ-ray. InFIG. 1, number average molecular weight of poly(3-hydroxybutyrate),which is a species of poly(β-hydroxyalkanoate)s, is plotted in relationto dose of the γ-ray emitted from cobalt 60. As apparent from the curveof FIG. 1, the number average molecular weight, which is 275,000 beforethe irradiation of the γ-ray, would decrease in accordance with anincrease in the dose of the irradiation to 20,000, which is less thanone tenth of the initial molecular weight, by the irradiation of 10 Mrador the γ-ray. It would be readily appreciated that the molecular weightof the composition can be reduced to any desired degree by controllingthe dose of the γ-ray irradiation regardless of the number averagemolecular weight of the composition before the γ-ray treatment.

The poly(3-hydroxybutyrate) would also undergo a decrease in itsmolecular weight when it is heated to a temperature in excess of about160° C. although its melting point is 180° C. In FIG. 2, number averagemolecular weight of the poly(3-hydroxybutyrate) is plotted in relationto the period of the heat treatment. According to the curves of FIG. 2,the number average molecular weight would be reduced to about one fourthof its initial value upon heat treating at 175° C. for 20 minutes, andto about one half of its initial value upon treating at 190° C. for 1minute.

Similar results were obtained for 3-hydroxybutyrate-3-hydroxyvaleratecopolymer and 3-hydroxybutyrate-4-hydroxybutyrate copolymer although theresults are not depicted.

The molecular weight of the composition can be adjusted to any desireddegree by a heat treatment as well as the irradiation with γ-ray. Itshould be noted, however, that the molecular weight can not be increasedby any of such methods. The poly(3- and the poly(4-hydroxyalkanoate)would also undergo a decrease in their molecular weight when they aretreated in an acidic solution such as sulfuric acid, hydrochloric acid,hypochlorous acid, or perchloric acid; or in an alkaline solution suchas sodium hydroxide or potassium hydroxide, and their number averagemolecular weight can be similarly reduced to the desired value byadequately selecting the conditions of the treatment to thereby adjustthe period required for their biodegradation.

Some experimental examples are hereinafter described.

EXPERIMENT 1

Poly(3-hydroxybutyrate) (number average molecular weight, Mn of 275,000)purchased from Aldrich Corporation in an amount of 0.6 g was fullydissolved in 30 ml of chloroform (guaranteed grade; manufactured by WakoPharmaceutical K.K.). The resulting solution was cast into a glass Petridish to obtain a film having a thickness of from 50 to 70 μm afterevaporation of the chloroform. The thus obtained film was irradiatedwith 1 Mrad of γ-ray emitted from cobalt 60. The number averagemolecular weight was then reduced to 100,000. The number averagemolecular weight was measured by liquid chromatography using LC-6Amanufactured by Simadzu Seisakusho Ltd. having secured thereto a column,Shodex GPC-80M manufactured by Showa Denko K.K. using a differentialrefractometer for the detector, solvent of chloroform, and a standard ofpolystyrene.

EXPERIMENT 2

Into 500 ml Sakaguchi flask (shaking flask) was poured a mediumcomprising 1 g of yeast extract (manufactured by DIFCO corporation), 1 gof polypeptone (manufactured by Nippon Pharmaceutical K.K.), 0.5 g ofmeat extract (Kyokuto Pharmaceutical Industries K.K.), and 0.5 g ofammonium sulfate (manufactured by Wako Pharmaceutical K.K.) dissolved in100 ml of distilled water. The medium was inoculated with Alcaligeneseutrophus H16 (ATCC 17699), which is a hydrogen bacteria, closed with acotton plug, and then cultivated at 30° C. for 2 days under shaking. Thethus propagated bacteria of 10 Sakaguchi flasks were collected by acentrifugation at 6,000 rpm for 15 minutes. Another medium was preparedby adding 1.0 ml of 20wt/vol % magnesium sulfate, 1.0 ml of the mineralsolution shown in Table 1, and 20 g of fructose (Kanto Chemical K.K.) toa phosphate buffer solution, pH 7.5 containing 14.0 ml of 0.5M potassiumdihydrogenphosphate and 124.0 ml of 0.25M disodium hydrogenphosphate per11 buffer solution. The thus prepared medium was poured into a 2.6 l jarfermentor (manufactured by Marubishi Bioengeneering K.K.), and thebacteria which had been collected by the centrifugation were transferredinto the jar fermenter. Cultivation was carried out at 30° C. for 48hours at a stirring blade-rotating rate of 500 rpm and a bubbling rateof 1 ml/min. After completing the cultivation, the propagated bacteriawere collected by centrifugation at 6,000 rpm for 15 min. The thuscollected bacteria were washed with water and lyophilized. Into 2 l ofchloroform was added 11.2 g of the thus lyophilized bacteria, and thesuspension was stirred at room temperature for 24 hours to extract thepolymer product. The extract-containing solution was filtered to removeinsoluble bacteria components, and the filtrate was then dropped intoabout 10 volumes of n-hexane (first grade; manufactured by WakoPharmaceutical K.K.) to precipitate the polymer. The thus precipitatedpolymer was confirmed to be poly(3-hydroxybutyrate) by measuring with ¹H-NMR (nuclear magnetic resonance spectrometer, EX 90; manufactured byJEOL Ltd.) The polymer product was also evaluated for its number averagemolecular weight by gel chromatography to be 775,000. Upon irradiationof the polymer product with 10 Mrad of γray emitted from cobalt 60, thenumber average molecular weight was reduced to 80,000.

                  TABLE 1                                                         ______________________________________                                        Composition of the mineral solution (in 1 l of 0.1N HCl)                      ______________________________________                                        CoCl.sub.2                                                                              119.0  mg      NiCl.sub.2.6H.sub.2 O                                                                  118.0 mg                                    FeCl.sub.3                                                                              9.7    g       CrCl.sub.3                                                                              62.2 mg                                    CaCl.sub.2                                                                              7.8    g       CuSO.sub.4.5H.sub.2 O                                                                  156.4 mg                                    ______________________________________                                    

EXPERIMENT 3

The poly(3-hydroxybutyrate) synthesized in Experiment 2 was heat treatedby placing it in an oven at 190° C. for 10 minutes. The resultingpolymer had a number average molecular weight of 120,000.

EXPERIMENT 4

The procedure of Example 2 was repeated except that the fructose wasreplaced with sodium 4-hydroxybutyrate (manufactured by AldrichCorporation) to produce 1.2 g of 3-hydroxybutyrate-4-hydroxybutyratecopolymer (comprising 20% by mole of 4-hydroxybutyrate unit) having anumber average molecular weight of 467,000. The thus produced copolymerproduct was added to a 100 ml solution comprising 1 volume of aqueoussolution of sodium hypochroride (manufactured by Wako PharmaceuticalK.K.) and 1 volume of distilled water, and the suspension was heated to50° C. for 2 hours. The resulting product had a number average molecularweight of 182,000.

EXPERIMENT 5

The procedure of Example 2 was repeated except that the fructose wasreplaced with valeric acid (first grade; manufactured by WakoPharmaceutical K.K.) to produce 3.8 g of3-hydroxybutyrate-3-hydroxyvalerate copolymer (comprising 63% by mole of3-hydroxyvalerate unit) having a number average molecular weight of225,000. The thus produced copolymer product was irradiated with 3 Mradof γ-ray emitted from cobalt 60. The resulting product had a numberaverage molecular weight of 50,000.

The results of the Experiments are summarized in Table 2.

                  TABLE 2                                                         ______________________________________                                                           MW                 MW                                      Exp. Polymer       before   Type of   after                                   No.  structure     treatment                                                                              treatment treatment                               ______________________________________                                        1    poly(3-hydroxy                                                                              275,000  1 Mrad γ-ray                                                                      100,000                                      butyrate)                                                                2    poly(3-hydroxy                                                                              775,000  10 Mrad γ-ray                                                                      80,000                                      butyrate)                                                                3    poly(3-hydroxy                                                                              775,000  190° C., 10 min.                                                                 120,000                                      butyrate)                                                                4    3-hydroxybutyrate-                                                                          467,000  sodium    182,000                                      4-hydroxybutyrate      hypochloride,                                          copolymer              50° C., 2 h.                               5    3-hydroxybutyrate-                                                                          225,000  3 Mrad γ-ray                                                                       50,000                                      3-hydroxyvalerate                                                             copolymer                                                                ______________________________________                                    

EXPERIMENT 6

Film pieces of about 50 μm thick with a size of 1×1 cm were preparedfrom the polymers produced in Experiments 1 to 5 by solvent casting. Thefilm pieces were buried in the back of a rat under its skin. After oneyear of the burial, the film pieces were retrieved and inspected.

Upon burial for one year, no substantial decrease in mechanical strengthof the each film was recognized. Each film, however, had undergone aconsiderable decrease in its number average molecular weight. The timethat would be required for undergoing a substantial decrease in themechanical strength was estimated from the data of the decrease in thenumber average molecular weight of the each film. The results are shownin Table 3.

COMPARATIVE EXPERIMENT 7

The poly(3-hydroxybutyrate) synthesized in Experiment 2 which had notbeen subjected to the γ-ray irradiation was subcutaneously buried in theback of a rat as in the case of Experiment 6. The molecular weight after1 year burial as well as the estimated time required for undergoingsubstantial decrease in the mechanical strength are shown in Table 3.The results indicate that, although the material had undergone somedecrease in its molecular weight, the time that would be required fordeterioration of the mechanical strength is as long as 20 years, andestimated period for complete disappearance (solubilization in water) ofthe material is as long as about 50 years. The material, therefore, cannot be deemed as essentially in vivo biodegradable.

COMPARATIVE EXPERIMENT 8

A polylactic acid film (number average molecular weight, Mn of 100,000;purchased from Polyscience K.K.) was subcutaneously buried in the backof a rat as in the case of Experiment 6. Upon inspection after 1 yearburial, the film had undergone a complete degradation to leave notraces. It is estimated that the film had experienced a substantialdecrease in its mechanical strength in several days. Degradation of thismaterial is too fast.

COMPARATIVE EXAMPLE 9

The poly(3-hydroxybutyrate) synthesized in Experiment 1 which had notbeen subjected to the γ-ray irradiation having a number averagemolecular weight of 275,000 was subcutaneously buried in the back of arat as in the case of Experiment 6. The molecular weight after 1 yearburial as well as the estimated time required for undergoing substantialdecrease in the mechanical strength are shown in Table 3. This materialwould require 5 years for substantial decrease in its mechanicalstrength, and this period is rather too long in practical point of view.Furthermore, this material would require a period of as long as fromfifteen or sixteen years to several decades for its completedisappearance (solubilization in water) to leave no debris, to renderthe material unusable.

                  TABLE 3                                                         ______________________________________                                               Molecular weight                                                                             Estimated time                                                 before after burial                                                                              required for reduction                                     burial for 1 year  in mechanical strength                              ______________________________________                                        (Exp. 1) 100,000  70,000      1.5 years                                       (Exp. 2)  80,000  68,000      1.5 years                                       (Exp. 3) 120,000  97,000      3 years                                         (Exp. 4) 182,000  100,000     2 years                                         (Exp. 5)  50,000  48,000      3 years                                         Comparative                                                                            775,000  563,000     20 years                                        Exp. 7                                                                        Comparative                                                                            100,000  not determined                                                                            several days                                    Exp. 8                                                                        Comparative                                                                            275,000  221,000     5 years                                         Exp. 9                                                                        ______________________________________                                    

EXPERIMENT 10

In 300 ml of chloroform (first grade; manufactured by WakoPharmaceutical. K.K.) were dissolved 30 g of the γ-ray irradiated poly(3-hydroxybutyrate) (number average molecular weight 100,000) and 9 g ofglycerol tributyrate (manufactured by Tokyo Chemical K.K.), and stirred.The solvent was distilled to produce a mixture of thepoly(3-hydroxybutyrate) and the glycerol tributyrate. The mixture wascut into pellets using scissors.

The thus produced pellets were charged in a small-sized, small-amountextruder (manufactured by Ohba Works K.K.) to extrude a string-likeextrudate from a nozzle having an inner diameter of 0.5 mm at a cylindertemperature of 178° C. and a die temperature of 176° C. Thestring-shaped extrudate was quenched immediately after the extrusion byusing liquid nitrogen. The quenched product was gradually (manually)stretched in a stretching machine at room temperature (about 29° C.) tomore than ten folds of its original length until it was almost at break.The resulting product was heat-treated in an oven at a temperature of60° C. for 3 hours to produce a flexible thread-like product (suture)having an outer diameter of 0.10 mm. The thus produced thread-likeproduct was sterilized with ethylene oxide gas, and attached to Bearstitching needle (round needle, strongly curved, #0) manufactured byKyowa Clock Industries K.K., to stitch an incision in the back of a rat.The suture was removed after two weeks. No specific problem was notedduring its use.

EXPERIMENT 11

The procedure of Experiment 6 was repeated except that thepoly(3-hydroxybutyrate) which had not under gone the the γ-rayirradiation (number average molecular weight, 275,000) was used toobtain a thread having an outer diameter of 0.10 mm. The thread was thenexposed to 1 Mrad of γ-ray irradiation. The resulting suture was usedfor stitching an incision at the back of a rat as in the case ofExperiment 10. The suture was removed after two weeks. No specificproblem was noted during its use. The number average molecular weightafter the sterilization was 100,000.

EXPERIMENT 12

A suture having an outer diameter of 0.08 mm was obtained by repeatingthe procedure of Experiment 6 except that the orientation conditionswere somewhat altered. The resulting suture was attached to Bearstitching needle (round needle, strongly curved, #0) to stitch anincision in intestine of an adult crossbred dog (weight, approx. 12 kg).Upon inspection after about one year by incising the abdomen, theincision had been successfully sutured, and the suture was located atits original place.

EXPERIMENT 13

The procedure of Experiment 6 was repeated except that the γ-rayirradiated 3-hydroxybutyrate-3-hydroxyvalerate copolymer prepared inExperiment 5 (number average molecular weight, 50,000) was used toproduce a suture. The thus produced suture was attached to a stitchingneedle to stitch the skin in the back of a rat. No specific problem wasnoted in the use of the suture.

EXPERIMENT 14

The 3-hydroxybutyrate-4-hydroxybutyrate copolymer after itstreatment(number average molecular weight, 182,000) was fabricated intoa film of 0.3 mm thick by solvent casting using chloroform. A film pieceof 30 mm×30 mm was cut out of the film, and inserted in abdominal cavityof a rat between the incision in the skin and the intestine for thepurpose of coalescence prevention. Upon inspection after one month, theincision had substantially healed, and no coalescence between theincision and the internal organs was recognized. It was also noted thatthe film had substantially retained its original shape.

EXPERIMENT 15

The procedure of the Experiment 6 was repeated except that the die ofthe extruder was replaced with a multi-hole die having 6 holes eachhaving a diameter of 0.3 mm to produce a thread-like product having anouter diameter in the range of from 0.01 to 0.03 mm. A 1 g portion ofthe thread-like product was placed in a test tube having an innerdiameter of 0.8 cm, and compressed with a glass rod inserted into thetest tube to fabricate a felt. The thus produced felt was placed insidethe abdominal cavity of a rat in contact with various organs. Nospecific problem was noted for one month.

Although Experiments 10 to 15 were carried out under in vivo conditionsusing animals, for example, rats, no degradation of the material wasrecognized in the period of up to 1 year. It is, however, conceivedthat, with the lapse of time, the materials would undergo a decrease intheir mechanical strength, and eventually, a complete deterioration toleave no trace.

The resin composition used for the flexible member for medical use ofthe present invention contains 0.10 to 60% by weight of a lipid compoundin addition to the above-described polyhydroxyalkanoate or a copolymerthereof, which is the main component.

Exemplary lipid compounds which may be blended with thepolyhydroxyalkanoate in the resin composition of the present inventioninclude monoglycerides, diglycerides, triglycerides, monocarboxylic acidesters, dicarboxylic acid monoesters, dicarboxylic acid diesters,dialcohol monoesters, dialcobol diesters, tricarboxylic acid monoesters,tricarboxylic acid diesters, tricarboxylic acid triesters.

More illustratively, exemplary monoglycerides include glycerolmonoacetate, glycerol monopropionate, glycerol monobutyrate, glycerolmonocaproate, glycerol monolaurate, glycerol monomyristate, glycerolmonopalmitate, glycerol monostearate, etc.;

diglycerides include glycerol diacetate, glycerol dipropionate, glyceroldibutyrate, glycerol dicaproate, glycerol dilaurate, glyceroldimyristate, glycerol dipalmitate, glycerol distearate, etc.; and

triglycerides include glycerol triacetate, glycerol tripropionate,glycerol tributyrate, glycerol tricaproate, glycerol trilaurate,glycerol tripalmitate, glycerol trimyristate, glycerol tristearate, etc.

Other carboxylic acid esters include an ester of a carboxylic acidhaving 2 to 30 carbon atoms with an alkylalcohol having 2 to 30 carbonatoms. More illustratively, exemplary preferred saturated or unsaturatedmonocarboxylic acid esters include n-amyl acetate, ethyl propionate,methyl caproate, ethyl crotoate, n-butyl oleate, etc;

saturated or unsaturated dicarboxylic acid monoesters include monomethylcebaciate, mono-n-butyl maleate, monoethyl terephthalate, etc.;

saturated or unsaturated dicarboxylic acid diesters include dimethylcebaciate, dimethyl terephthalate, di(2-ethylhexyl) phthalate,di-n-octyl phthalate, etc.;

tricarboxylic acid monoesters include monomethyl trimellitate,mono-n-butyl trimellitate, etc.;

tricarboxylic acid diesters include dimethyl trimellitate, dibutyltrimellitate, etc.;

tricarboxylic acid triesters include trimethyl trimellitate, tributyltrimellitate, etc.;

dialcohol monoesters include ethylene glycol monostearate, propyleneglycol monostearate, etc; and

dialcohol diesters include ethylene glycol distearate, propylene glycoldistearate, etc.

The lipid compounds as mentioned above may be either liquid or solid atnormal temperatures.

In the resin composition used for the flexible medical member of thepresent invention, the lipid compound as described above functions as aplasticizing agent or a flexibility-imparting agent for thepolyhydroxyalkanoate. The lipid compound, when mixed with thepolyhydroxyalkanoate, may also reduce the melting point of thepolyhydroxyalkanoate to enable the resin composition to be worked at alower temperature and prevent unnecessary decomposition of thecomposition. The workability of the resin composition is therebyimproved. In addition, such an inclusion of the lipid composition, whichis generally inexpensive, is advantageous in economic point of view.

In the resin composition, the lipid compound may comprise from 0.01 to60% by weight, and preferably, from 1 to 40% by weight of thecomposition. The lipid compound of a content of less than 0.01% byweight is insufficient for improving the physical properties of thepolyhydroxyalkanoate. The lipid compound of a content in excess of 60%by weight may induce phase separation of the lipid compound to detractfrom the physical properties of the resulting flexible medical member.

Mixing of the polyhydroxyalkanoate and the lipid compound may beeffected by such means as dissolution of the compounds in a suitablesolvent such as chloroform, methylene chloride, 1,2-dichloroethane, anddioxane, followed by stirring and evaporation of the solvent; andaddition the lipid compound to the polyhydroxyalkanoate using a mixingroll or an extruder under heating.

Such a resin composition which is utilized in the flexible medicalmember of the present invention is described in detail in JapanesePatent Application No. 2-76585 filed by the applicant of the presentinvention.

Use of a complex material comprising the above-described resincomposition in admixture with another resin is also adequate forfabricating the flexible medical member of the invention.

The resin which may be used for such a mixing is not limited to anyparticular species, and various conventional resins may be used inaccordance with the desired properties. Exemplary preferable resinsinclude polyethylene, polypropylene, polyvinyl chloride, polyvinylacetate, ionomer, polyacrylic acid, polyacrylate, polymethacrylic acid,polymethacrylate, polyvinyl alcohol, polystyrene, polyvinylidenechloride, polyethylene terephthalate, polybutyrene terephthalate, nylon,polycarbonate, polyethylene glycol, polypropylene glycol, fluororesin,and copolymers thereof.

As mentioned above, such a resin which is mixed with the above-describedresin composition may be adequately selected in accordance with thedesired properties. For example, the resin composition may be impartedwith mechanical durability by an addition of polyethylene terephthalate;and with a surface water repellency by an addition of a fluororesin.

When a complex material comprising the above-described resin compositionmixed with such a resin is utilized for the flexible medical member ofthe invention, the material may generally contain from about 1 to 70% byweight of such a resin, although the content of the resin may notnecessary fall within such a range.

In addition to such a resin, the resin composition may optionallyinclude a filler, a die, a pigment, a lubricant, an antioxidant, astabilizer, and the like.

Preparation of the complex material by the mixing of such a resin withthe above-described resin composition may be effected by such means asdissolution of the resins in a suitable solvent such as chloroform,methylene chloride, 1,2-dichloroethane, and dioxane, followed bystirring and evaporation of the solvent; and mixing of the resins usinga mixing roll or an extruder under heating.

At least a part of the flexible member for medical use of the presentinvention is fabricated from the above-described biodegradable resincomposition or a complex material comprising a mixture of such abiodegradable resin composition with various resins (which arehereinafter referred to as the biodegradable materials).

The medical member which is fabricated from such a biodegradablematerial is not limited to any particular type, and the biodegradablematerial may be used for fabricating any flexible medical member whichhas been fabricated from a flexible material such as a polyvinylchloride having added thereto a phthalic acid-based compound as aplasticizing agent, an elastomer, a rubber, or the like.

Furthermore, the configuration of the member fabricated from thebiodegradable material is not limited at all, and the medical member maybe a cylindrical member including a tube, a bag, a box, a columnarmember, a cone-shaped member, a film, a sheet, a thread, a woven ornonwoven fabric, or a molded article of other irregular configurations.

Examples of the medical member which may be fabricated from theabove-described biodegradable material include:

blood transfusion system, infusion system, tubings for blood circuitsand the like, connecting tubing, connector, manifold, drop cylinder,branched tube, stopcock, and the like;

blood bag, infusion bag, urinary bag, dialysis bag, perintestinalnutrient bag, and other liquid bags;

catheter to be introduced into urinary tract, digestive tract or otherbody cavities, and balloon catheter;

suture, mesh, patch, pledget, coalescence-preventing film, prosthesis,and other thread, fabric, or sheet-form products; and

staple, clip, and other molded articles.

The flexible member for medical use of the present invention has anexcellent biodegradability, and therefore, such members are particularlysuitable for disposable medical members.

It should be noted that the flexible member for medical use of thepresent invention does not have to be fabricated solely from theabove-described biodegradable material. It is also possible to fabricatesome parts of the flexible medical member from such a biodegradablematerial, and other parts from a conventional resin material. In thecase of a balloon catheter, for example, the biodegradable material maybe used for fabricating the balloon or the shaft, and other parts may befabricated from a conventional resin. In the case of aliquid-accommodating bag, the biodegradable material may be used for thebody of the bag while other parts including the connecting portions maybe fabricated from a conventional resin.

The flexible medical member may also comprise a laminate of theabove-described biodegradable material with another conventional resin.

The biodegradable material used for fabricating the flexible medicalmember of the present invention has thermoplastic properties. Therefore,the flexible medical member of the invention having a tubular, bag, orother configuration can be fabricated from the biodegradable material byany process used for conventional resins, for example, extrusionmolding, injection molding, vacuum molding, press-molding, and the like.An appropriate process may be selected in consideration of theconfiguration or usage of the resulting medical member as well asinstallation in which the resulting member is used. For example, amember in the form of a staple as shown in FIG. 3 can be fabricated bysuch means as injection molding.

The biodegradable material adapted to be used for the flexible medicalmember of the present invention can be fabricated into a string form byany of the conventional processes employed for extruding a string-likeproduct from conventional thermoplastic resins. For example, thematerial can be extruded from an extrusion molding machine having acylinder and a die which has been heated to a temperature 5° to 20° C.higher than the melting point of the biodegradable material to produce amono-filament or a multi-filament product.

The thus extruded string-like product, which in itself may constitute aflexible medical member of the present invention, may not be fullysufficient in its strength when used as a suture. In such a case, theextrudate may be subsequently stretched for orientation.

Such an orientation by stretching of the thus extruded product may becarried out, for example, by stretching the string-like extrudate inamorphous conditions in its axial direction at a temperature between theglass transition temperature (Tg) and the melting point (Tm) of thematerial, and subsequently crystallizing the thus stretched product. Thethus oriented product will have an increased strength.

The thus produced thread-like product may be fabricated into a braidedsuture, a woven fabric, a nonwoven fabric, or the like by anyconventional process including the one employing a braider or a weavingloom. A suture, a mesh, a patch, or a pledget may be readily fabricatedby such a process.

Beside the above-mentioned extrusion, a string-like product may befabricated from the biodegradable material by a so-called wet spinningprocess wherein the biodegradable material is dissolved in a solventsuch as chloroform and 1,2-dichloroethane, which is capable ofdissolving the biodegradable material, to prepare a solution at aconcentration of about 2 to 5%, and then extruding the thus preparedsolution into a coagulating solvent such as ethanol, methanol andn-hexane with a device having a nozzle such as a syringe to coagulatethe material in the string form. Such a process is also preferable.

As mentioned above, the biodegradable material is soluble in such asolvent as chloroform and 1,2-dichloroethane. Therefore, it can befabricated into a sheet or a film product by such means as casting. Thethus formed film may be used, for example, as a coalescence-preventingfilm.

When the biodegradable material is laminated with another resin toproduce a laminate, the biodegradable material may be dissolved in theabove-mentioned solvent, and the resulting solution may be dip-coated orroll-coated on the other resin material.

Illustrative methods of fabricating the flexible medical member of thepresent invention using the above-described resin composition arebriefly set forth in the following description.

(1) Fabrication of a Suture

The resin composition used in the present invention has a melting point,and therefore, it can be thermally molded by such means as extrusionmolding. For example, such an extrusion molding may be carried out in asmall-sized, small-amount extruder (manufactured by Ohba Works K.K.)having mounted thereto a mono-hole die at a temperature 5° to 20° C.higher than the melting point of the material to extrude a mono-filamentproduct. For extruding a multi-filament product, the mono-hole die maybe replaced with a multi-hole die. Alternatively, a string-form productmay be fabricated by a so-called wet spinning wherein the material ofthe invention is dissolved in chloroform or dichloromethane to prepare asolution having a concentration of 2 to 5% and the solution issubsequently extruded into a solvent such as n-hexane, methylalcohol orethylalcohol from a syringe-like nozzle to thereby coagulate the polymerin the string form. If desired, the resulting string-form product may bebraided in a braider to produce a braided suture. The string-formproduct which has been fabricated by either of the above-mentionedprocesses is in amorphous conditions, and therefore, it may be furtheroriented by stretching the product in its axial direction at atemperature in the vicinity of or higher than the glass transitiontemperature (Tg) and retaining the stretched state for a period of timesufficient for promoting a full crystallization. The thus orientedproduct will be a suture having a sufficient strength.

If desired, the thus produced suture may be further subjected to asurface treatment which is carried out for conventional sutures such ascoating with calcium stearate. Also, the suture may be attached to astitching needle by such means as fitting to prepare a needle-attachedsuture.

(2) Fabrication of a Mesh and a Pledget

The thread which has been prepared by the above-describedsuture-fabricating process may be fabricated into a fabric with aweaving loom, or alternatively, fabricated into a Nonwoven fabric bywadding or by using a feltizer. The thus produced woven or nonwovenfabric is subsequently cut into a mesh or a pledget.

(3) Fabrication of a Staple and a Clip

As mentioned above, the material of the present invention has a meltingpoint, and therefore, it can be thermally molded by injection molding toproduce a staple or a clip of the desired shape by using a moldingtemperature which is 10° to 30° C. higher than the melting point of thematerial.

The flexible member for medical use of the present invention which hasbeen fabricated as described above will be used for the predeterminedpurposes after sterilization. Sterilization may be carried out by any ofvarious conventional methods such as sterilization in an autoclave, UVsterilization, sterilization with an ionizing radiation, for example,γ-ray or electron beam, gas sterilization using, for example, ethyleneoxide, and sterilization using a reagent, for example, an alcohol.

EXAMPLES

The present invention is hereinafter described in further detail byreferring to illustrative examples of the flexible member for medicaluse according to the present invention.

EXAMPLE 1

Poly(3-hydroxybutyrate) (Mw of 670,000; manufactured by AldrichCorporation) and glycerol trilaurate (manufactured by Tokyo ChemicalK.K.) in a weight ratio of 80:20 were dissolved in chloroform, andstirred. The resulting solution was cast to obtain a sheet of 2 mm thickafter evaporation of the chloroform.

The resulting sheet was cut with a cutter to produce pellets. Thepellets were used for the starting material in the subsequent extrusionmolding at a die temperature of 175° C. in an extrusion-molding machine,Plastomil (manufactured by Toyo Precision Machines K.K.) to produce atubing having an outer diameter of 6 mm and an inner diameter of 4 mm.

No trouble was noted in the molding of the tubing. The resulting tubingwas a tough, flexible tubing.

The thus produced flexible tubing was used to assemble an infusionsystem 10 as shown in FIG. 4. In the infusion system 10, only theflexible tubing 12 was the flexible medical tubing of the presentinvention, and other member were conventional members. The infusionsystem was placed in a conventional package bag, and after sealing ofthe bag, it was sterilized by irradiating 1 Mrad of γ-ray emitted fromcobalt 60.

The thus prepared infusion system 10 was used for an infusion of 500 mlof physiological saline (Terumo Physiological Saline; manufactured byTerumo K.K.) at a flow rate of 10 ml/min. No specific problem was notedduring the infusion.

The infusion system 10 after its use was buried in soil at Nakai-cho,Ashigarakami-gun, Kanagawa, Japan, and retrieved from the soil burialafter six months. The flexible tubing 12 which had been prepared fromthe flexible medical material of the present invention underwent acomplete degradation in soil to leave no original shape.

In contrast, the members of the infusion system comprising conventionalmaterials such as bottle needle, drip cylinder, and clamp fully retainedtheir original shapes after the soil burial.

EXAMPLE 2

The pellets were produced by repeating the procedure of Example 1 exceptthat glycerol triacetate (manufactured by Tokyo Chemical K.K.) was usedinstead of the glycerol trilaurate, and the mixing ratio of thepoly(3-hydroxybutyrate) to the glycerol triacetate was 70:30. The thusproduced pellets were used for the starting material in the subsequentextrusion molding, which was carried out by repeating the procedure ofExample 1 except that the extrusion was conducted at a die temperatureof 160° C. to produce a flexible tubing having an outer diameter of 6 mmand an inner diameter of 4 mm. No trouble was noted in the molding ofthe tubing. The resulting tubing was a highly flexible, soft tubing.

The thus produced flexible tubing was used to assemble an infusionsystem similar to the one produced in Example 1, and the infusion systemwas subjected to an experiment similar to Example 1. No specific problemwas noted during its use. When retrieved from the soil burial for sixmonths, the flexible tubing underwent a complete degradation to leave nooriginal shape while other members of the infusion system comprisingconventional materials such as bottle needle, drip cylinder, and clampfully retained their original shapes.

COMPARATIVE EXAMPLE 1

The procedure of Example 1 was repeated except that no glyceroltrilaurate was used in the preparation of the tubing. The resultingtubing, which was far from being flexible, became fractured uponassembly of the infusion system, and therefore, an infusion system couldnot be assembled by using such a tubing.

EXAMPLE 3

Poly(3-hydroxybutyrate) (manufactured by Aldrich Corporation) andglycerol trilaurate (manufactured by Tokyo Chemical K.K.) in a weightratio of 70:30 were dissolved in chloroform, and stirred. The procedureof Example 1 was repeated to produce pellets.

The pellets were used for the starting material in the subsequentblown-film extrusion at a die temperature of 165° C. in anextrusion-molding machine used in Example 1 to which a blown-film diehad been mounted to produce a sheet of 0.4 mm thick. The resulting sheetwas heat-sealed to fabricate a flexible bag 14 as shown in FIG. 5. Tothe thus fabricated bag was connected a tubing produced in Example 2.

No specific trouble was noted in the extrusion. The resulting flexiblebag 14 was sufficiently soft.

The flexible bag 14 was filled with 100 ml of physiological saline(Terumo Physiological Saline; manufactured by Terumo K.K.), and then,sterilized in an autoclave at 121° C. for 20 minutes.

The bag was stored for one month at room temperature, and then, visuallyinspected. Upon inspection, no specific change or inclusion of foreignmatter in the content of the bag (physiological saline) was noted. Also,the flexible bag 14 retained its flexibility to an extent that it wascapable of enduring a use under normal conditions.

The physiological saline was then discharged from the flexible bag 14,and the thus emptied flexible bag 14 was buried in a soil at Nakai-cho,Ashigarakami-gun, Kanagawa, Japan. When the bag was retrieved from thesoil burial of six months, the bag 14 had undergone a completedegradation to leave no original shape.

COMPARATIVE EXAMPLE 2

To 100 parts by weight of straight polyvinyl chloride (S1001,manufactured by Kanegafuchi Chemical Industry Col, Ltd.) was blended 50parts by weight of dioctyl phthalate and other conventionally employedadditives such as an antioxidant. The procedure of Example 3 was thenrepeated to produce a non-rigid polyvinyl chloride sheet by blown-filmextrusion. The resulting non-rigid polyvinyl chloride sheet wassubjected to a high-frequency sealing to produce a flexible bag similarto the one shown in FIG. 3.

The thus produced flexible bag was buried in soil for six months in themanner similar to Example 3. No specific change in the appearance wasrecognized upon visual inspection after retrieval from the soil.

EXAMPLE 4

The procedure of Example 1 was repeated except that a(3-hydroxybutyrate) (3-hydroxyvalerate) copolymer (molar fraction of3-hydroxybutyrate of 83% Mw of 800,000; manufactured by AldrichCorporation) was used instead of the poly(3-hydroxybutyrate), and theextrusion was conducted at a die temperature of 150° C. to produce aflexible medical tubing of the present invention.

The thus produced flexible tubing was used to assemble an infusionsystem similar to the one produced in Example 1, and the infusion systemwas subjected to an experiment similar to Example 1. No specific problemwas noted during its use. When retrieved from the soil burial for sixmonths, the flexible tubing underwent a complete degradation to leave nooriginal shape while other members of the infusion system comprisingconventional materials such as bottle needle, drip cylinder, and clamphad retained their original shapes.

EXAMPLE 5

Poly(3-hydroxybutyrate) (Mw=670,000; manufactured by AldrichCorporation), glycerol tributyrate (manufactured by Tokyo ChemicalK.K.), polyethylene terephthalate (Sunpet 3150G; manufactured by AsahiChemical Industry Co., Ltd.), and an antioxidant (Irganox 1010;manufactured by Chiba-Geigy Corporation) in a weight ratio of 80:20:20:1were blended, and the blend was directly charged in theextrusion-molding machine used in Example 1 to extrude a bar-shapedextrudate, which was cut into pellets. The thus produced pellets weresubjected to a blown-film extrusion at a die temperature of 215° C. toproduce a blown-film extruded sheet of 0.4 mm thick.

A flexible bag was produced from the resulting sheet by repeating theprocedure of Example 3. No trouble was noted in the above-describedprocess.

The resulting flexible bag had a higher toughness as well as higherresistance to breaking and scratching compared to the one produced inExample 3.

The flexible bag was filled with physiological saline, sterilized in anautoclave, stored for one month at room temperature, and then, visuallyinspected to find no specific change in the bag or in the contentthereof.

The physiological saline was then discharged from the flexible bag, andthe thus emptied flexible bag was buried in soil for six months as inthe case of Example 1. When the bag was retrieved from the soil burial,it had undergone a substantial degradation to leave tatters. A smallamount of powder was also recognized, which was estimated to be thepolyethylene terephthalate.

EXAMPLE 6

Poly (3-hydroxybutyrate) (Mw=670,000; manufactured by AldrichCorporation) and glycerol tributyrate (manufactured by Tokyo ChemicalK.K.) in a weight ratio of 80:20 were dissolved in chloroform, andstirred. The resulting solution was cast to obtain a sheet of 2 mm thickafter evaporation of the chloroform.

The resulting sheet was cut with a cutter to produce pellets. Thepellets were used for the starting material in the subsequent extrusionin a small-sized, small-amount extruder (manufactured by Ohba WorksK.K.) to extrude a string-like extrudate from a nozzle having an innerdiameter of 0.5 mm at a cylinder temperature of 178° C. and a dietemperature of 176° C. The string-shaped extrudate was quenchedimmediately after the extrusion by using liquid nitrogen.

The fully quenched string-like product was stretched in a stretchingmachine at room temperature (about 29° C.) to more than ten folds of itsoriginal length until it was almost at break.

The resulting product was heat-treated in an oven at a temperature of60° C. for 3 hours to produce a flexible thread-like product (suture)having an outer diameter of 0.1 mm.

The thus produced thread-like product was sterilized with ethylene oxidegas, and attached to Bear stitching needle (round needle, stronglycurved, #0) manufactured by Kyowa Clock Industries K.K., to stitch anincision in the back of a rat. The suture was removed after two weeks.No specific problem was noted during its use.

A remaining length of the suture was buried in soil (at a depth of about10 cm from the soil surface) at Nakai-cho, Ashigarakami-gun, Kanagawa,Japan, and retrieved from the soil burial after two months. It wasobserved that the suture had undergone a substantial degradation in soilto scarcely leave its original shape.

EXAMPLE 7

The procedure of the above Example 6 was repeated except that glyceroltricaproate (Tokyo Chemical K.K.) was used instead of the glyceroltributyrate to produce a flexible suture having an outer diameter of 0.1mm.

An incision in the back of a rat was stitched as in the case of Example6. No specific problem was recognized in the use of the suture. Uponburial of the suture in soil as in the case of Example 6, the sutureunderwent a substantial degradation to scarcely leave its originalshape.

EXAMPLE 8

The procedure of the above Example 6 was repeated except that glycerolmonostearate (Tokyo Chemical K.K.) was used instead of the glyceroltributyrate to produce a flexible suture having an outer diameter of0.11 mm.

An incision in, the back of a rat was stitched as in the case of Example6. No specific problem was recognized in the use of the suture. Uponburial of the suture in soil as in the case of Example 6, the sutureunderwent a substantial degradation to scarcely leave its originalshape.

EXAMPLE 9

The procedure of the above Example 6 was repeated except that the die ofthe extrusion molding machine having a single hole having a diameter of0.5 mm was replaced with the one having 6 holes each having a diameterof 0.3 mm to produce a thread-like product having an outer diameter offrom 0.01 to 0.03 mm after the orientation treatment by stretching.

A 1 g portion of the thread-like product was placed in a test tubehaving an inner diameter of 0.8 cm, and compressed with a glass rodinserted into the test tube to obtain a felt-like product.

The thus produced felt-like product was placed inside the abdominalcavity of a rat in contact with various organs. No specific problem wasnoted in the rat after one month.

The remaining felt-like product was buried in soil for two months as inthe case of Example 6. The product then underwent a substantialdegradation to scarcely leave its original shape.

EXAMPLE 10

Staples shown in FIG. 1 was fabricated with a small-sized, small-amountinjection molding machine (manufactured by Arbourg Corporation) usingthe pellets prepared by repeating the procedure of Example 6.

The thus fabricated staples were used to close an incision in the backskin of a rat. The staples could be used without inducing any specifictrouble. The staples were buried in soil as in the case of Example 6.After two months of the burial in soil, the staples underwent asubstantial degradation to scarcely leave their original shape.

EXAMPLE 11

The pellets in an amount of 1 g prepared by repeating the procedure ofExample 7 were dissolved in 30 ml of chloroform to produce a cast filmof 0.6 mm thick on a Petri dish. A piece of the film with a size of30×30 mm was cut out of the thus produced cast film, and then,sterilized with ethylene oxide gas. The sterilized film was inserted inabdominal cavity of a rat between the incision in the skin and theintestine for the purpose of preventing coalescence of the incision withthe internal organs.

Upon inspection of the incision after one month by incising the abdomenof the rat, the incision had substantially healed, and no coalescencebetween the incision and the internal organs was recognized. It was alsonoted that the cast film had substantially retained its original shape.The cast film which was not used was buried in soil as in the case ofExample 6. In two months, the film had undergone a substantialdegradation to scarcely leave its original shape.

INDUSTRIAL UTILITY

The flexible member for medical use of the present invention isfabricated from a predetermined resin composition which has an excellentbiodegradability. Consequently, the flexible medical member of thepresent invention has an excellent biodegradability, and upon burial insoil or disposal in sea after sterilization, it will undergo adegradation in environment in a relatively short period. Therefore, theflexible medical member of the invention would not cause anenvironmental pollution.

In addition, the flexible member for medical use of the presentinvention has good workability, high cost performance, sufficientcompatibility with ecosystem, and excellent biocompatibility. Therefore,it is suitable for various medical applications including disposableflexible medical members and implants.

We claim:
 1. A flexible member for medical use selected from the groupconsisting of a blood bag, an infusion bag, a dialysis bag and aperintestinal nutrient bag wherein said flexible member comprises a bodyand at least one fluid port, and said body is fabricated from a resincomposition comprising:at least one member selected from the groupconsisting of a polyhydroxyalkanoate and a copolymer thereof; and aglyceride, said glyceride comprising 0.01 to 60% by weight of said resincomposition.
 2. The flexible member for medical use according to claim1, wherein said polyhydroxyalkanoate is selected from the groupconsisting of a poly(3-hydroxyalkanoate), a poly(4-hydroxyalkanoate),and a poly(5-hydroxyalkanoate).
 3. The flexible member for medical useaccording to claim 2, wherein said glyceride is selected from the groupconsisting of monoglyceride, diglyceride and triglyceride.
 4. Theflexible member for medical use according to claim 3, wherein saidglyceride is glycerol tributyrate.
 5. The flexible member for medicaluse according to claim 1, wherein said resin composition furthercomprises a resin component selected from the group consisting ofpolyethylene, polypropylene, polyvinyl chloride, polyvinyl acetate, anionomer, polyacrylic acid, polyacrylate, polymethacrylic acid,polymethacrylate, polyvinyl alcohol, polystyrene, polyvinylidenechloride, polyethylene terephthalate, polybutyrene terephthalate, nylon,polycarbonate, polyethylene glycol, polypropylene glycol, a fluororesinand a copolymer thereof,said resin composition comprising 1 to 70% byweight of said resin component.
 6. The flexible member for medical useaccording to claim 5, wherein resin component is polyethyleneterephthalate.
 7. A flexible member for medical use according to claim1, wherein said body and said port comprise said resin composition.